Journal Article

Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration

Le Maitre, Christine Lyn, Jordan-Mahy, Nikki, Nicklin, Martin J H, Phillips, Kate Louise Eve

2013

Overview

Objectives Interleukin 1 (IL-1) is potentially important in the pathogenesis of intervertebral disc (IVD) degeneration; increasing production of matrix degradation enzymes and inhibiting matrix synthesis. Although IL-1 polymorphisms have been linked to increased risk of IVD degeneration, it is still unclear whether IL-1 drives IVD degeneration in vivo or is a secondary feature of degeneration. Here, we investigated whether IVD degeneration could be induced spontaneously by the removal of the natural inhibitor of IL-1 (IL-1 receptor antagonist) in mice that lack a functional IL-1rn gene. Methods Histological staining and immunohistochemistry was performed on BALB/c IL-1rn+/+ and IL-1rn−/− mice to examine degeneration and to localise and detect IL-1, matrix metalloproteinases (MMP)3, MMP7, a disintigrin and MMP with thrombospondin motifs (ADAMTS)4 protein production. In addition, IVD cells were isolated using collagenase and proliferation potential determined. Results IL-1rn−/− knockout mice displayed typical features of human disc degeneration: loss of proteoglycan and normal collagen structure and increased expression of matrix degrading enzymes: MMP3; MMP7 and ADAMTS4. Histological grade of degeneration increased in IL-1rn−/− mice which was more evident within older mice. In addition IVD cells isolated from IL-1rn−/− mice displayed reduced proliferation potential. Conclusions Here, we show that IL-1rn−/− mice develop spinal abnormalities that resemble characteristic features associated with human disc degeneration. The current evidence is consistent with a role for IL-1 in the pathogenesis of IVD degeneration. The imbalance between IL-1 and IL-1Ra which is observed during human IVD degeneration could therefore be a causative factor in the degeneration of the IVD, and as such, is an appropriate pharmaceutical target for inhibiting degeneration.

• Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism,Elsevier Limited
• Subject: ADAM Proteins - metabolism / ADAMTS4 Protein / Age / Animals / Binding sites / Biomedical research / Chondrocytes / Cybernetics / Cytokines / Digital cameras / Disease Activity / Disease Models, Animal / Enzymes / Genotype & phenotype / Interleukin 1 Receptor Antagonist Protein - genetics / Interleukin-1 - metabolism / Intervertebral Disc Degeneration - etiology / Intervertebral Disc Degeneration - pathology / Low Back Pain / Matrix Metalloproteinase 3 - metabolism / Matrix Metalloproteinase 7 - metabolism / Mice / Mice, Knockout / Pathogenesis / Procollagen N-Endopeptidase - metabolism / Rodents / Spine - pathology / Studies